The present invention provides a process for the production, enrichment and/or isolation of pure alpha-tocotrienol enriched tocotrienol compositions from naturally occurring extracts, and to the alpha-tocotrienol-containing product produced by the process. This process can be performed without chromatography, or with minimal use of chromatography, and is economically feasible on a commercial scale.
Tocopherols and tocotrienols are molecules characterized by a 6-chromanol ring structure and a side chain at the C-2-position. Tocotrienols possess a 4′, 8′, 12′ trimethyltridecyl unsaturated phytol side chain with the presence of double bonds at 3′, 7′, and 11′ positions of the side chain, while tocopherols have a saturated side chain. The geometry of each of these double bond sites is trans (also referred to as E) in all four natural tocotrienols. There are four naturally occurring tocotrienols, d-alpha-, d-beta-, d-gamma-, and d-delta-tocotrienol. The four naturally occurring tocotrienols have the (R) absolute configuration at the C-2 chroman ring position.
R1 R2R3Alpha- tocotrienolmethylmethylmethyl Beta- tocotrienolmethylHmethyl Gamma- tocotrienolHmethylmethyl Delta- tocotrienolHHmethyl Alpha- tocopherolmethylmethylmethyl Beta- tocopherolmethylHmethyl Gamma- tocopherolHmethylmethyl Delta- tocopherolHHmethyl
Tocotrienols are present in the oils, seeds, and other parts of many plants used as foods (see pp. 99-165 in L. Machlin, ed., “Vitamin E: A Comprehensive Treatise” for a discussion of the occurrence of tocotrienols in foods). Tocotrienol-containing concentrates can be prepared from certain plant oils and plant oil by-products such as rice bran oil or palm oil distillate. For examples of such isolation processes, see for instance A. G. Top et al., U.S. Pat. No. 5,190,618 (1993) or Tanaka, Y. et al., Japanese Patent No. JP2003-171376 (2003).
There is a problem inherent in obtaining tocotrienols from natural sources, in that the tocotrienol yield from such processes is a mixture of varying amounts of all of the natural tocotrienols and tocopherols. In order to obtain a pure member of the tocotrienol family, it has been necessary to resort to very expensive procedures such as preparative scale reverse-phase chromatography or simulated moving bed chromatography. For an example of such a purification process, see M. Kitano et al., Japanese Patent No. 2003-02777 (2003) or Burger et al., U.S. Pat. No. 4,603,142.
The synthesis of tocotrienols in the natural form, having the (2R) chiral configuration and trans double bonding at the proper locations in the side chain, has also been proven to be of considerable difficulty.
Syntheses of various members of the tocotrienol family in the d,l- or (RS)-form have been published; see for example Schudel et al., Helv. Chim. Acta (1963) 46, 2517 2526; H. Mayer et al., Helv. Chim. Acta (1967) 50, 1376 11393; H.-J. Kabbe et al., Synthesis (1978), 888 889; M. Kajiwara et al., Heterocycles (1980) 14, 1995 1998; S. Urano et al., Chem. Pharm. Bull. (1983) 31, 4341 4345, Pearce et al., J. Med Chem. (1992), 35, 3595 3606 and Pearce et al., J. Med Chem. (1994). 37, 526 541. None of these reported processes lead to the natural form of the tocotrienols, but rather produce racemic mixtures. Syntheses of natural form d-tocotrienols have been published. See for example, J. Scott et al., Helv. Chim. Acta (1976) 59, 290 306, Sato et al. (Japanese Patent 63063674); Sato et al. (Japanese Patent No. JP 01233278) and Couladouros et al (U.S. Pat. No. 7,038,067).
Tocotrienols occur largely in palm oil, rice bran oil, and barley. While synthetic and natural tocopherols are readily available in the market, the supply of natural tocotrienols is limited, and generally comprises a mixture of tocotrienols. Crude palm oil which is rich in tocotrienols (800-1500 ppm) offers a potential source of natural tocotrienols. Carotech, located in Malaysia, is an industrial plant able to extract and concentrate tocotrienols from crude palm oil. Carotech uses a molecular distillation process (employing ultra-high vacuum and very low temperature) in its production plant. This process (see U.S. Pat. No. 5,157,132) allows Carotech to extract phytonutrients such as the Tocotrienol Complex (Tocomin®, a registered trademark of Carotech for extracts and concentrates of palm tree fruits) from the crude palm oil. Tocomin®-50 typically comprises about 25.32% mixed tocotrienols (7.00% alpha-tocotrienol, 14.42% gamma tocotrienol, 3.30% delta tocotrienol and 0.6% beta tocotrienol), 6.90% alpha-tocopherol and other phytonutrients such as plant squalene, phytosterols, co-enzyme Q10 and mixed carotenoids.
Additional commercially available products that may be used in the present invention are for example, Nu Triene Tocotrienol® (30% content, a product of Eastman Chemical Company), various Oryza® tocotrienol products of different tocotrienol concentrations from Oryza Oil & Fat Co. Ltd including Oryza tocotrienol-70 with 70% total tocopherol/tocotrienol content, and a total tocotrienol content of 40% including 14% of alpha-tocotrienol and 24% gamma-tocotrienol, and Oryza tocotrienol-90 with 90% total tocopherol/tocotrienol content and a total tocotrienol content of 60%; Golden Hope Plantations Berhad Tocotrienol oil (70% content), Davos Life Science TRF (63% content), Ginnoway™ tocotrienol concentrate from palm and rice oil from Beijing Gingko Group, Gold Trie® a product of Sime Darby Biorganic Sdn Bhd and Palm Nutraceuticals Sdn Bhd (89% content). Delta Tocotrienol-92® (92% pure by HPLC) is a commercially available product from Beijing Gingko Group that may be also used in the present invention.
Methods for isolation or enrichment of tocotrienol from certain plant oils and plant oil by-products have been described in the literature, but these methods generally produce mixtures of natural tocols in varying amounts and are not economically feasible on a commercial scale. As mentioned above, in order to obtain a pure member of the tocotrienol family, it has been necessary to resort to expensive procedures such as preparative scale reversed-phase chromatography or simulated moving bed chromatography. For some examples of such isolation and purification processes, see for instance Top A. G. et. al., U.S. Pat. No. 5,190,618; Lane R et al., U.S. Pat. No. 6,239,171; Bellafiore, L. et al U.S. Pat. No. 6,395,915; May, C. Y et al., U.S. Pat. No. 6,656,358; Jacobs, L et al, U.S. Pat. No. 6,838,104; Sumner, C et al. Int. Pat. Pub. WO 99/38860, or Jacobs, L. Int. Pat. Pub. WO 02/500054.
Production of d-alpha tocopherol from natural plant sources has been described in U.S. Pat. No. 4,977,282, where natural plant sources having Vitamin E activity of a concentrate of mixed tocopherols that might include tocotrienols are transformed into alpha-tocopherol. In this isolation, alpha tocopherol is enriched after amino-alkylating the mixed tocopherols which are then reduced by catalytic hydrogenation to convert the mixture of the non-alpha tocopherol tocols into alpha-tocopherol. In this process, any tocotrienols present would be hydrogenated to tocopherol. See Netscher et al. (2007) Eur J. Org. Chem 1176-1183
Because of the similar molecular and retention characteristics of the various individual tocopherols and tocotrienols, separation of the individual compounds has been proven difficult and not commercially viable. Although the process for the production of alpha-tocotrienol has been described, it is only available in pure form at very high prices (e.g., USD$672 for 100 mg of ≥98% pure alpha-tocotrienol from Fluka Chemical Company in October, 2009).
In light of the above, there remains a need for a method of producing the naturally occurring alpha-tocotrienol in a pure form that is economically feasible on a commercial scale. Such a process would minimize the number of processing steps required, and would not require, or would minimize the use of, chromatographic separations.